ArticleMolecular psychiatry2021
A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 27 citations in OpenAlex.
- Protocadherin γC4 regulates neuronal survival and dendritic self-avoidance.Communications biology · 2026Article
- Human iPSC-derived glutamatergic neurons with pathogenic KCNQ2 variants display hyperactive bursting phenotypes.Neurobiology of disease · 2025Article
- Targeting Histone H3K9 Methyltransferase G9a as a Potential Therapeutic Strategy for Neuropsychiatric Disorders.Medicinal research reviews · 2025Review
- Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.Brain : a journal of neurology · 2025Article
- Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community.Cell reports methods · 2025Article
- Mosaic H3K9me3 at BREACHes predicts synaptic gene expression associated with fragile X syndrome cognitive severity.bioRxiv : the preprint server for biology · 2025Article
- In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds.Nature neuroscience · 2025Article
- Chromatin modifiers in neurodevelopment.Frontiers in molecular neuroscience · 2025Review
- Opposite and Differently Altered Postmortem Changes in H3 and H3K9me3 Patterns in the Rat Frontal Cortex and Hippocampus.Epigenomes · 2024Article
- Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.Cell reports · 2024Article
- Loss of NSD2 causes dysregulation of synaptic genes and altered H3K36 dimethylation in mice.Frontiers in genetics · 2024Article
- Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder.Current neuropharmacology · 2024Review
- Post-transcriptional regulation of the transcriptional apparatus in neuronal development.Frontiers in molecular neuroscience · 2024Review
- Emergence and influence of sequence bias in evolutionarily malleable, mammalian tandem arrays.BMC biology · 2023Article
- CTCF barrier breaking by ZFP661 promotes protocadherin diversity in mammalian brains.bioRxiv : the preprint server for biology · 2023Article
- IntelliCage: the development and perspectives of a mouse- and user-friendly automated behavioral test system.Frontiers in behavioral neuroscience · 2023Review
- Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance.Nature reviews. Molecular cell biology · 2022Review
- Structure, Activity and Function of the Suv39h1 and Suv39h2 Protein Lysine Methyltransferases.Life (Basel, Switzerland) · 2021Review
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Authors and funding
28 authors at 13 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.
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